A comprehensive understanding of the mechanisms associated with the generation and modulation of immunological T cell memory will lead to a better understanding of not only how the immune system controls viral infections but also causes immune-mediated pathology. Our studies with viruses in murine systems have focused on virus-specific memory T cell populations, which demonstrate plasticity in antigen recognition and in their ability to accommodate new memory T cell populations. Memory T cells laid down as a consequence of one infection can influence protective immunity and immunopathology associated with a second unrelated virus. We have referred to this phenomenon as T cell-dependent heterologous immunity and immunopathology. The focus of this grant is to develop a better understanding of the mechanisms associated with the induction of heterologous immunity, specifically the role cross-reactive memory T cell responses and cytokines play in decreasing or augmenting viral replication and altering immunopathology. We have identified potential cross-reactive epitopes between viruses, developed both systemic and respiratory infection model systems, and assembled suitable reagents and molecular techniques. This proposal will use several viruses, but continues to focus on lymphocytic chorimeningitis (LCMV) and Pichinde (PV) viruses, distantly related arenaviruses whose T cell responses are well defined, and on the poxvirus vaccinia (W), which is used as a vaccine for smallpox and as a recombinant vaccine and vector for many antigens. With this baseline information and techniques we will be able to perform an in depth analysis of the role that cross-reactive T responses play in heterologous immunity during a series of viral infections. Specific Aim #1. Test whether CDS T cell responses to the nearly identical cross-reactive epitope, NP205, between LCMV and PV influence immunodominance hierarchy, TCR usage, and disease outcome. Specific Aim #2. Test whether a matrix of cross-reactive memory CDS T cells between LCMV, PV and W influence immunodominance hierarchy, TCR usage, and disease outcome. Specific Aim #3. Examine the mechanisms involved in augmented viral replication and immunopathology during LCMV or MCMV infection of influenza-immune mice. Specific Aim #4. Define the role of cytokines in mediating heterologous immunity.